Staphylococcus aureus is a bacterium that causes significant disease burden in hospitals and communities. With a yearly toll of 300,000 hospitalizations and 11,000 deaths caused by S. aureus in the United States alone, it is clear that the clinical therapeutic standards implemented to treat these infections are insufficient. The poor efficacy associated with current treatment strategies stems in part from a rise in antibiotic resistance among infectious isolates, as well as acquisition of novel virulence traits that promote survival within inhospitable host environments. In addition, S. aureus has evolved for centuries alongside its human host as a transient commensal of the skin and nasal cavity. As a consequence of this intimate association, the bacterium has become remarkably well equipped with a broad and highly redundant arsenal of factors that allow it to evade major host defenses and promote survival. Thus, S. aureus can flourish in nearly every host tissue upon breaching its commensal niche. If we are to successfully combat S. aureus in the clinic it is imperative that we understand the diverse mechanisms used by the bacterium to evade host defenses and adapt to growth restriction in vivo. In this vein, our laboratory aims to decipher novel mechanisms by which S. aureus effectively usurps host innate immunity and adapts to nutritional deficiencies in order to cause disease. The preliminary data in this grant indicate tha de novo biosynthesis and salvage of the metabolite lipoate by S. aureus is critical for survival of the bacterium in specific tissues during infection. Furthermore, we have determined that de novo biosynthesis of lipoate promotes disease persistence through anti-inflammatory properties that restrict macrophage activation. Within the host, bioavailable lipoate is low and bacteria must adapt to acquire the metabolite during periods of prolonged restriction. S. aureus appears to use unique lipoate biosynthetic and salvage mechanisms to offset this nutritional restriction and foster replication. Thus, our data highlight two novel hypotheses associated with lipoate salvage/biosynthesis and pathogenesis: (i) S. aureus lipoate biosynthesis suppresses innate immune cell activity allowing escape from immune defenses and (ii) the lipoate acquisition mechanisms of S. aureus allow the bacterium to overcome critical nutritional deficiencies in the host thereby enabling optimal fitness during infection at diverse sites. The Aims of this application are to: (1) Define the lipoate biosynthesis and salvage pathways of S. aureus; (2) Investigate how lipoate-containing factors suppress macrophage activation; and (3) Evaluate how lipoate biosynthesis and salvage contribute to metabolic adaptation and host inflammation.